Abstract text (incl. figure legends and references)
Introduction
Patients suffering from malignant melanoma, breast cancer and lung cancer are at high risk of developing brain metastases (BM), which are at this time incurable and have devasting consequences for quality of life, already at the time of the diagnosis. The underlying mechanisms of brain colonisation of the metastatic cancer cells, immune cell infiltration and interaction with the unique brain microenvironment are yet to be uncovered and are challenging to study in preclinical models.
Objectives
The focus of our work is to better understand how metastatic cancer cells derived from extracranial tumors surpass the blood-brain-barrier, seed the brain and how the cross-talk with immune-cells and brain-resident cells influences BM growth and development. Here, we set out to target relevant cellular processes with brain-penetrant therapeutic agents at an early stage of brain colonisation in order to prevent the formation of large, uncurable brain metastases.
Materials & methods
Our preclinical models of breast cancer and melanoma brain metastases enable to monitor long-term the dynamic development of BM in mice using intravital microscopy (IVM) through chronic cranial window. In order to achieve high-resolution insight into these processes, we perform intravital correlative microscopy, combining IVM, x-ray micro-CT and 3D electron microscopy.
Results
Here, I will disuss different projects aiming to reduce BM growth in vivo by by targeting early and critical events during brain colonisation. Intravital correlative microscopy was used to reveal how metastatic cancer cells cross the blood-brain-barrier. We found that this process is MMP9 dependent, and that the main source of the MMP9 is the cancer cell itself (Karreman et al, in revision). Moreover, we demonstrate that low-dose PI3K/mTOR inhibition in a preventative setting hinders melanoma brain metastatic growth in vivo (Tehranian et al, Neuro-oncology, 2021). Finally, using newly developed mouse models, we identified a new route for T cells to enter the brain and target melanoma brain metastases (Messmer et al, submitted for publication).
Conclusion
There is a pressing need to develop new therapeutic approaches against BM development. Targeting the earliest steps of this disease enables to circumvent more aggressive and often ineffective treatments. Intravital (correlative) microscopy on various models of brain metastases enabled us to uncover important mechanisms of brain colonisation and thus inform new treatment strategies.